Huntington's disease prevalence in Asia: a systematic review and meta-analysis.

INTRODUCTION: The epidemiological studies on Huntington's disease (HD) in the Asian population suggest that prevalence rates are significantly lower than in the Western population. We conducted a systematic review of epidemiological studies of HD in Asia to compare the level of impact of the disease on the Asian population. METHODS: Original articles and reviews about HD prevalence in the Asian population were found through databases such as Embase, Medline, and PsychInfo. Relevant articles were analysed by scrutinising of references, including specific key words. A meta-analysis was performed on prevalence rates to find the degree of similarities with I2. Point Prevalence was measured as the number of people affected by HD in a 100,000 population and expressed as Point Prevalence (PP)= Number of people affected/100,000 with 95% Confidence Intervals (CI95). RESULTS: Results from the random-effect meta-analysis show the highest point prevalence of HD in the Middle East with PP=4.0 (CI95=2.90-5.30). The lowest point prevalence was found in the Chinese population with PP=0.25 (CI95=0.16-0.36). Europe remains at a high prevalence compared to Asian countries with PP=1.00 (CI95=0.82-1.19). The overall prevalence in Asia is PP=0.70 (CI95=0.44-1.0). CONCLUSION: Our study reveals that HD disease affects the population of Asia to a lesser extent than in Europe. The plausible explanation for differences in prevalence is that in some countries, the affected individuals will not self-refer to HD screening for fear of social stigma, negative influence in marriage, and lack of genetic and neurological testing. Another explanation is that studies that used genetic testing exclusively were able to identify the CAG repeats, subgroups of CAG repeat A1 & A2, and haplogroup C, which has less predisposition to high HD prevalence in Asians compared to the Caucasian population.

Pooling of primary care electronic health record (EHR) data on Huntington's disease (HD) and cancer: establishing comparability of two large UK databases.

OBJECTIVES: To explore whether UK primary care databases arising from two different software systems can be feasibly combined, by comparing rates of Huntington's disease (HD, which is rare) and 14 common cancers in the two databases, as well as characteristics of people with these conditions. DESIGN: Descriptive study. SETTING: Primary care electronic health records from Clinical Practice Research Datalink (CPRD) GOLD and CPRD Aurum databases, with linked hospital admission and death registration data. PARTICIPANTS: 4986 patients with HD and 1 294 819 with an incident cancer between 1990 and 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: Incidence and prevalence of HD by calendar period, age group and region, and annual age-standardised incidence of 14 common cancers in each database, and in a subset of 'overlapping' practices which contributed to both databases. Characteristics of patients with HD or incident cancer: medical history, recent prescribing, healthcare contacts and database follow-up. RESULTS: Incidence and prevalence of HD were slightly higher in CPRD GOLD than CPRD Aurum, but with similar trends over time. Cancer incidence in the two databases differed between 1990 and 2000, but converged and was very similar thereafter. Participants in each database were most similar in terms of medical history (median standardised difference, MSD 0.03 (IQR 0.01-0.03)), recent prescribing (MSD 0.06 (0.03-0.10)) and demographics and general health variables (MSD 0.05 (0.01-0.09)). Larger differences were seen for healthcare contacts (MSD 0.27 (0.10-0.41)), and database follow-up (MSD 0.39 (0.19-0.56)). CONCLUSIONS: Differences in cancer incidence trends between 1990 and 2000 may relate to use of a practice-level data quality filter (the 'up-to-standard' date) in CPRD GOLD only. As well as the impact of data curation methods, differences in underlying data models can make it more challenging to define exactly equivalent clinical concepts in each database. Researchers should be aware of these potential sources of variability when planning combined database studies and interpreting results.

Economic Burden of Huntington's Disease in China: Results from a National-Wide Cross-Sectional Study.

BACKGROUND: Huntington's disease (HD) poses a significant socio-economic burden globally. Existing research on HD's economic burden predominantly comes from Western settings, leaving a gap in data from Asian countries. This study aimed to assess the economic burden of HD in China and identify cost-driving factors. METHODS: This study used data from a 2019 nationwide cross-sectional survey of individuals affected by rare diseases in China. Data included socio-demographic characteristics, income, disease stage, health and social insurance coverage status, treatment-seeking behaviour, and costs. Logistic regression and linear regression were used to explore potential contributors to treatment-seeking behaviour and associated costs. RESULTS: Of the 269 individuals with HD included in this study, 80.6% were actively seeking treatment. The average annual direct medical cost, direct non-medical cost, and indirect cost were 3,265.65, 805.82, and 801.97 Euros, respectively. Compared to participants with early-stage HD, those with middle- or advanced-stage HD reported higher direct medical costs (coefficient 1,612.70, 95% confidence interval [CI]: [141.92, 3,083.48] and 2,398.58, 95% CI: [791.16, 4,006.00], respectively). However, the disease stage was not significantly associated with direct non-medical costs or indirect costs. CONCLUSIONS: This study provides crucial insights into the economic burden of HD in China. It emphasises a need for targeted policies that better cater to the financial needs of HD patients.

Frailty and Associated Environmental Factors Only Have Small Effects on Age of Onset in Huntington's Disease.

BACKGROUND: Over one third of age of onset variation in Huntington's disease is unexplained by CAG repeat length. In Alzheimer's disease, frailty partly modulates the relationship between neuropathology and dementia. OBJECTIVE: We investigated whether a multi-domain frailty index, reflecting non-genetic factors in Huntington's disease, similarly modulates the relationship between CAG repeat length and age of onset. METHODS: We created a frailty index assessing comorbidities, substance abuse, polypharmacy, and education. We applied multiple linear regression models to 2,741 subjects with manifest Huntington's disease from the Enroll-HD cohort study, including 729 subjects with late-onset (post-60 years) disease, using frailty index or constituent item scores and CAG repeat length as independent variables. We used actual and "residual" ages of onset (difference between actual and CAG-based predicted onset) as dependent variables, the latter offsetting the increased time available to accumulate comorbidities in older subjects. RESULTS: Higher frailty index scores were associated with significantly lower residual ages of onset in the late-onset subgroup (p = 0.03), though the effect was small (R2 = 0.27 with frailty as a predictor vs. 0.26 without). Number of comorbidities was also associated with significantly lower residual ages of onset in the late-onset subgroup (p = 0.04). Drug abuse and smoking were associated with significantly earlier ages of onset in the whole cohort (p < 0.01, p = 0.02) and late-onset subgroup (p < 0.01, p = 0.03). CONCLUSIONS: The impact of non-genetic factors on age of onset, assessed using a frailty index or separately, in Huntington's disease is limited.

Apoptosis Genes as a Key to Identification of Inverse Comorbidity of Huntington's Disease and Cancer.

Cancer and neurodegenerative disorders present overwhelming challenges for healthcare worldwide. Epidemiological studies showed a decrease in cancer rates in patients with neurodegenerative disorders, including the Huntington disease (HD). Apoptosis is one of the most important processes for both cancer and neurodegeneration. We suggest that genes closely connected with apoptosis and associated with HD may affect carcinogenesis. We applied reconstruction and analysis of gene networks associated with HD and apoptosis and identified potentially important genes for inverse comorbidity of cancer and HD. The top 10 high-priority candidate genes included APOE, PSEN1, INS, IL6, SQSTM1, SP1, HTT, LEP, HSPA4, and BDNF. Functional analysis of these genes was carried out using gene ontology and KEGG pathways. By exploring genome-wide association study results, we identified genes associated with neurodegenerative and oncological disorders, as well as their endophenotypes and risk factors. We used publicly available datasets of HD and breast and prostate cancers to analyze the expression of the identified genes. Functional modules of these genes were characterized according to disease-specific tissues. This integrative approach revealed that these genes predominantly exert similar functions in different tissues. Apoptosis along with lipid metabolism dysregulation and cell homeostasis maintenance in the response to environmental stimulus and drugs are likely key processes in inverse comorbidity of cancer in patients with HD. Overall, the identified genes represent the promising targets for studying molecular relations of cancer and HD.

A Cost Model for Neurological Diseases in Puerto Rico: Parkinson's Disease, Alzheimer's Disease and Huntington's Disease.

OBJECTIVE: This article proposes an engineering-economics model to determine the total cost of a neurological disease along its temporal progression. The objective was to develop a planning tool faithful to the reality of this type of ailment as well as to that of Puerto Rico (PR). METHODS: The proposed model organizes a given neurological disease into 3 progressive phases of deterioration; in each, the model collects the typical associated costs and adjusts them based on their value over time. This way, the total cost of the ailment is calculated and its present day dollar value expressed. Model verification was carried out using data from Puerto Rico related to Parkinson's, Alzheimer's, and Huntington's diseases. RESULTS: The method demonstrated here considered Parkinson's disease in PR. Our model calculated a total annual cost of $64,915 for a patient at the medium stage. This figure is larger than estimates from other authors, which fall between $41,689 and $51,600 for the USA. This difference is partially due to the proposed model considering the individual's opportunity cost of the loss of productive years, an original contribution of our work. CONCLUSION: A neurological disease is one in which an individual goes through progressive phases of deterioration that will require significant economic resources. The model proposed here is designed across the commonalities between Alzheimer's, Parkinson's, and Huntington's diseases and illustrated using costs from PR. As an additional contribution, it allows the consideration of the opportunity cost of lost productivity, a characteristic that makes it more realistic.

[Huntington disease in the Valencian Region]. / La enfermedad de Huntington en la Comunitat Valenciana.

INTRODUCTION: Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. OBJECTIVE: Describe the geographical, age and sex distribution of HD in the Valencia Region (VR) and determine its prevalence and mortality. MATERIALS AND METHODS: Cross-sectional study for the period 2010-2018. Confirmed cases of HD were identified through the Rare Disease Information System of the VR. Sociodemographic characteristics were described, and the prevalence and mortality rate were obtained. RESULTS: 225 cases were identified, 50.2% women. 52.0% lived in the province of Alicante. 68.9% were verified by their clinical diagnosis. The median age at diagnosis was 54.1 years, 54.7 years in men and 53.0 years in women. The prevalence in 2018 was 1.97/100,000 inhabitants (95%; CI: 0.39-2.37), showing a no significant increasing trend, overall and by sex. 49.8% died, 51.8% men. The median age at death was 62.7 years, being lower in men than in women. The mortality rate in 2018 was 0.32/100,000 inhabitants (95%; CI: 0.32-2.28), with no statistically significant differences. CONCLUSIONS: The prevalence obtained was within the range estimated by Orphanet (1-9/100,000). A difference between sexes was observed in the diagnosis age. Men are the group with the highest mortality and the earliest age of death. It is a disease with high mortality with an average of 6.5 years between diagnosis and death.

TITLE: La enfermedad de Huntington en la Comunitat Valenciana.Introducción. La enfermedad de Huntington (EH) es un trastorno raro neurodegenerativo caracterizado por movimientos coreicos involuntarios, trastornos conductuales y psiquiátricos, y demencia. Objetivo. Describir la distribución geográfica, etaria y por sexo de la EH en la Comunitat Valenciana (CV), y determinar su prevalencia y mortalidad. Materiales y métodos. Estudio transversal en el período 2010-2018. Se identificaron, a través del Sistema de Información de Enfermedades Raras de la CV, los casos confirmados de EH. Se describieron las características sociodemográficas, y se obtuvieron la prevalencia y la tasa de mortalidad. Resultados. Se identificaron 225 casos, un 50,2% mujeres. El 52% residía en la provincia de Alicante. Un 68,9% se verificó por su diagnóstico clínico. La mediana de edad en el momento del diagnóstico fue 54,1 años, 54,7 en los hombres y 53 en las mujeres. La prevalencia en 2018 fue de 1,97/100.000 habitantes ­intervalo de confianza al 95% (IC 95%): 0,39-2,37­. El 49,8% falleció, un 51,8% hombres. La mediana de edad en el momento del fallecimiento fue de 62,7 años, y fue inferior en los hombres que en las mujeres. La tasa de mortalidad en 2018 fue de 0,32/100.000 habitantes (IC 95%: 0,32-2,28) y no se observaron diferencias estadísticamente significativas, ni en conjunto ni por sexos, durante el período de estudio. Conclusiones. La prevalencia obtenida estaba dentro del rango estimado por Orphanet (1-9/100.000). Se observó una diferencia por sexos en la edad de diagnóstico. Los hombres son el grupo de mayor mortalidad y de edad de fallecimiento más temprana. Es una enfermedad con alta mortalidad, con una media de 6,5 años entre el diagnóstico y el fallecimiento.

A systematic review and meta-analysis of depression and apathy frequency in adult-onset Huntington's disease.

Depression and apathy are associated with decreased functional capacity in Huntington's disease (HD) but frequency of depression and apathy in HD is largely unknown. Systematic literature searching was conducted across 21 databases until 30 June 2021. Inclusion criteria was limited to clinician-rated assessments of depression and apathy and adult-onset HD. Inverse-variance heterogeneity meta-analyses were conducted exploring depression and apathy frequency within individuals from families affected by HD, and within individuals with confirmed HD gene-positive status. Screening identified 289 articles for full-text review; nine remained for meta-analysis. Depression frequency in the lifetime in adults affected by or at-risk for HD was 38%, I2 = 99%. Apathy frequency in the lifetime in adults affected by or at-risk for HD was 40%, I2 = 96%. The robustness of the findings improved when limiting the analysis to gene-positive individuals only where apathy was found to be slightly more common than depression, 48% and 43% respectively. Future studies may consider reporting results from juvenile-onset HD and adult-onset HD cohorts separately to further explore phenotypic profiles.

Huntington's Disease in Chile: Epidemiological and Genetic Aspects.

INTRODUCTION: Huntington's disease (HD) is a neurodegenerative, autosomal dominant disabling condition due to an expansion of the CAG trinucleotide in the HTT gene. Motor, psychiatric, and cognitive disorders characterize it. Chilean reports on HD in the era of molecular diagnosis were wanted. METHODS: This is a retrospective analysis of a prospective cohort of patients with HD seen at the Center for Movement Disorders (CETRAM) in Chile between 2013 and 2019. Sociodemographic, genotype, and neuropsychiatric features were investigated. RESULTS: One hundred three probands with HD were identified. The majority (63.1%) were born in the metropolitan region, followed by the VIII and V regions with 8.73% and 7.76%, respectively. When pedigrees were analyzed, ninety unrelated families encompassing 1,007 individuals were identified; among relatives, other 35 manifested HD, and 106 died of HD. Besides, five hundred seventy-nine individuals were at genetic risk. The minimum estimated prevalence of HD in Chile in 2019 was 0.72 × 100,000 inhabitants. The mean CAG repeats (CAGR) of 47.2 ± 10.74 for the expanded allele and 17.93 ± 2.05 for the normal allele. The mean age of onset was 41.39 ± 13.47 years. Juvenile cases represented 7.8% of this cohort, and 4.9% had a late onset. There was a negative correlation between the age of onset and the CAGR of the expanded allele (r =-0.84 p < 0.0001). Besides, 79.6% had a family history of HD. CONCLUSIONS: This is the first report characterizing genetics, motor, and neuropsychiatric features in patients with HD in Chile. The mean length of CAGR expansion of the abnormal allele was similar to previous reports in North America (i.e., Mexico and Canada) and higher than that reported in the neighboring country of Argentina. According to previous estimations, the minimal prevalence of HD in Chile may be lower than expected.

Longitudinal analysis of neuropsychiatric symptoms in a large cohort of early-moderate manifest Huntington's disease patients.

BACKGROUND: The relationship between neuropsychiatric symptoms (NPS) and other clinical dimensions in Huntington's disease (HD) is controversial. This longitudinal study analyzed the association between NPS and motor, cognitive and functional aspects of the disease along with other variables related to its clinical onset and progression. METHODS: 639 early-moderate HD patients were assessed longitudinally (mean: 4.95 visits/5 years). Generalized linear mixed models were used to explore associations between NPS and the aforementioned aspects. Other variables previously reported as significant in smaller or cross-sectional studies were included in the models. RESULTS: Significant associations found included a negative linear relationship between presence of depressed mood and illness duration (7.2% odds reduction of being depressed per year), a 7.6% increase in the odds of having irritability with increased chorea scores, a negative association (4.3% reduction in odds) between age at onset and aggression (i.e. earlier onset was related to a higher probability of having aggressive behaviors) and a negative association between irritability and the interference component of the Stroop test (3% odds change). Total functional capacity (TFC) was the most frequently associated factor with NPS, with apathy and perseverative behavior having the strongest relations with TFC (22% and 18% increases in odds per unit reduction in TFC respectively). CONCLUSIONS: With the exception of irritability, NPS are not related to motor or cognitive variables in early-moderate HD. Total functional capacity (TFC) is the most frequently associated factor with NPS, with apathy and perseverative behavior having the strongest relations with TFC.

Comorbidities and clinical outcomes in adult- and juvenile-onset Huntington's disease: a study of linked Swedish National Registries (2002-2019).

BACKGROUND: Huntington's disease (HD) is a rare, neurodegenerative disease and its complex motor, cognitive and psychiatric symptoms exert a lifelong clinical burden on both patients and their families. OBJECTIVE: To describe the clinical burden and natural history of HD. METHODS: This longitudinal cohort study used data from the linked Swedish national registries to describe the occurrence of comorbidities (acute and chronic), symptomatic treatments and mortality in an incident cohort of individuals who either received the first diagnosis of HD above (adult onset HD; AoHD) or below (juvenile-onset HD; JoHD) 20 years of age, compared with a matched cohort without HD from the general population. Disease burden of all individuals alive in Sweden was described during a single calendar year (2018), including the occurrence of key symptoms, treatments and hospitalizations. RESULTS: The prevalence of HD in 2018 was approximately 10.2 per 100,000. Of 1492 individuals with a diagnosis of HD during 2002 and 2018, 1447 had AoHD and 45 had JoHD. Individuals with AoHD suffered a higher incidence of obsessive-compulsive disorder, acute psychotic episodes, pneumonia, constipation and fractures compared with matched controls. Individuals with JoHD had higher incidence rates of epilepsy, constipation and acute respiratory symptoms. Median time to all-cause mortality in AoHD was 12.1 years from diagnosis. Patients alive with HD in Sweden in 2018 displayed a pattern of increased clinical burden for a number of years since diagnosis. CONCLUSIONS: This study demonstrates the significant and progressive clinical burden in individuals with HD and presents novel insights into the natural history of JoHD.

The oral manifestations of Huntington's disease: A systematic review of prevalence.

OBJECTIVES: The objective of this systematic literature review was to provide a complete panorama of the oral manifestations of Huntington's disease (HD). MATERIALS AND METHODS: Databases were searched, and original research studies or case report manuscripts up to May 2021 were included using keywords that describe HD combined with words related to oral health; MeSH terms were used exclusively. No time or language restrictions were applied. RESULTS: Twenty-two investigations (12 original articles and 10 case reports) regarding oral manifestations of HD were included. The subjects examined in the selected research articles were dental health, coordination of oral structures, speech, dysphagia, and swallowing alterations. The case reports described dental treatment procedures, oromandibular dyskinesia, dysphagia, and speech alterations. CONCLUSIONS: The oral manifestations of HD were found to be associated with the advance of the disease in that the more severe the HD, the worse the alterations affecting the oral cavity. Dysphagia, dysarthria, masticatory problems, oral health impairment, and choreiform movements involving the tongue and other orofacial muscles were the main manifestations of HD in the oral cavity. The PROSPERO systematic review registration number of this study is CRD42021238934.

Apathy and Depression in Huntington's Disease: Distinct Longitudinal Trajectories and Clinical Correlates.

OBJECTIVE: Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease resulting in motor disturbances, dementia, and psychiatric symptoms. Apathy is a common manifestation and rated as one of the most impactful by patients and caregivers. It can often be difficult to distinguish from depression because of shared features and frequent overlap. This study examined the longitudinal trajectories and clinical correlates of apathy and depression. METHODS: Data were drawn from the Cooperative Huntington Observational Research Trial, a prospective, multicenter observational study that recruited 1,082 patients with HD. Measures of cognition, function, neuropsychiatric symptoms, motor function, and medication use were completed annually over 5 years. RESULTS: Overall, 423 patients (39%) showed evidence of apathy at study baseline, and both the prevalence and overall severity of apathy increased over time. Depression, by contrast, affected a similar proportion at baseline, although levels remained relatively stable over the study. Apathy was associated with worse cognition, function, neuropsychiatric symptoms, and motor symptoms. Depression was associated with worse neuropsychiatric symptoms, suicidal ideation, and independence but not other outcomes after control for other variables. CONCLUSIONS: Apathy in HD increased over time and was associated with worse clinical outcomes. These associations were independent of depression and other clinical variables. The findings highlight the need to distinguish between apathy and depression given their distinct implications for prognosis and management.

Psychotropic medication use in Huntington's disease: A retrospective cohort study.

BACKGROUND: Whereas the treatment of motor symptoms in Huntington's disease (HD) receives much attention, less is known about the treatment of neuropsychiatric symptoms. OBJECTIVE: We aim to give an overview of psychotropic drug use in the treatment of neuropsychiatric symptoms across disease stages in HD. METHODS: We conducted a descriptive cross-sectional study of psychotropic drug prescriptions in a large longitudinal database of HD patients, Enroll HD. Across disease stages, the number of prescriptions per medication class, as well as the registered indications for these prescriptions were listed, and compared with that in gene negative participants. RESULTS: Of the 8967 included HD patients, 80% were using at least one psychotropic drug, compared to 27% of gene negative participants. In HD patients, 51% of all drug prescriptions was for psychotropic drugs. The average number of psychotropic drugs used per patient increased from 1.3 in the premanifest stage to 2.5 in stage 5. With progressing disease stages, the proportion of antidepressant drug prescriptions gradually decreased from 74.1% of all prescriptions to 27.3%, and antipsychotic drug prescriptions increased from 7.0% to 38.7%. In line with this, depression and anxiety as listed indications for prescription decreased with advancing disease stages (from 63.0% to 31.5% and from 30.0% to 15.4% respectively), whereas irritability and psychosis increased (from 3.1% to 28.6% and from 0.9% to 16.0% respectively). CONCLUSIONS: Psychotropic medication is widely prescribed in HD, for various indications. Antidepressant use decreases proportionally and antipsychotic use increases with advancing disease stages, suggesting a relative decrease in prevalence of anxiety and depression over disease stages on one hand, and a relative increase in prevalence of irritability and delusions on the other.

Huntington's disease: Mortality and risk factors in an Australian cohort.

INTRODUCTION: There has not been any examination of the risk factors associated with mortality in Huntington's Disease (HD) in an Australian cohort. METHOD: This retrospective study included inpatients admitted to a specialist neuropsychiatry service in Melbourne, Australia. HD status was based on genetic testing. Risk factors included age of onset, CAG repeat length and neuroimaging. Mortality data was acquired through the Australian Institute of Health and Welfare National Death Index. RESULTS: The cohort included 83 participants, with 44 (53%) deceased. The median age of death was 59 years and median survival was 18.8 years from onset age (median 41.0 years). CAG repeat length (median 44.0, IQR 42.5, 47.0) was inversely correlated with age of onset (r = -0.73) and age at death (r = -0.80) but was not correlated with mortality status. There was no difference in functional and cognitive assessments, nor brain volumes, in the alive group compared to the deceased group. There were more people who were alive who had a positive family history of a psychiatric condition (p = 0.006) or dementia (p = 0.009). Standardised mortality ratios demonstrated a 5.9× increased risk of death for those with HD compared to the general population. CONCLUSIONS: This is the first study to examine risk factors of mortality in HD in an Australian cohort. Median survival in our cohort is consistent with previous studies in HD, and markedly reduced compared to the general Australian population. CAG repeat length was not associated with mortality suggesting that non-genetic factors contribute to mortality status and warrant further investigation.